New interplay between interstitial and alveolar macrophages explains pulmonary alveolar proteinosis (PAP) induced by indium tin oxide particles.

Occupational exposure to indium tin oxide (ITO) particles has been associated with the development of severe lung diseases, including pulmonary alveolar proteinosis (PAP). The mechanisms of this lung toxicity remain unknown. Here, we reveal the respective roles of resident alveolar (Siglec-F AM) and recruited interstitial (Siglec-F IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1α (not GM-CSF) deficiency and Siglec-F AM (not Siglec-F IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In by Siglec-F IM. In contrast, Siglec-F AM weakly phagocytose or dissolve ITO particles, but are sensitive to released In through the expression of the transferrin receptor-1 (TfR1). Blocking pulmonary Siglec-F IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In release, Siglec-F AM depletion, and PAP formation. Restoration of IL-1-related Siglec-F AM also prevented ITO-induced PAP. We identified a new mechanism of secondary PAP development according to which metal ions released from inhaled particles by phagocytic IM disturb IL-1α-dependent AM self-maintenance and, in turn, alveolar clearance.